1) An unknown primary is defined as squamous cell carcinoma presenting in cervical lymph nodes with no identifiable primary tumor site after examination. This clinical entity is known as carcinoma of unknown primary (CUP). 2) Evaluation involves physical examination, imaging like PET-CT, and panendoscopy with biopsies of suspicious sites to identify the occult primary tumor. Bilateral tonsillectomy and tongue base biopsy can identify occult tumors in the tonsillar crypts in many cases. 3) Treatment depends on tumor stage but often involves combined modality treatment with surgery, radiation, and/or chemotherapy aimed at locoregional control while minimizing morbidity.

1. Dr HIMANSHU SONI
Fellow in Head & Neck Surgical Oncology - FHNO
Fellow in CranioMaxilloFacial Trauma – AOMSI
Oral and Maxillofacial Surgeon

2.  An unknown primary is defined as a squamous cell carcinoma (SCC)
presenting in a lymph node or nodes in the neck with no primary index site
in the head and neck having been identified.
 The term carcinoma of unknown primary (CUP) should be used if no
evidence of primary tumor is found after adequate
 clinical examination
 fibreoptic endoscopy,
 imaging investigation which includes fluorine 18-labelled deoxyglucose
positron emission tomograpgy ideally with CT fusion imaging
 biopsy of putative mucosal sites

3. • CUP accounts for 5%-10% of all tumours
• 3–5% of head and neck cancers presented as cervical squamous cell
carcinomas of unknown primary
• Squamous cell carcinoma (SCC) is the most common histotype, followed by
adenocarcinoma, undifferentiated carcinoma and other malignancies (for
example, lymphoma and melanoma)
Bell RB, Andersen PE, Fernandes RP. Oral, head and neck oncology and reconstructive
surgery.2018

4. • About 1% of all head and neck malignancies are accounted for by
metastasis from a remote primary site
• most frequent identifiable sites include-
• breast ,lung, gastrointestinal tract, genitourinary tract, and, uncommonly,
the central nervous system
• Breast - 2.3% to 4.3%
• Lung - varies from 1.5 to 35%
• Esophagus - 20% to 30% of esophageal carcinomas present with cervical
node involvement
López F, Rodrigo JP, Silver CE, Haigentz Jr M, Bishop JA, Strojan P, Hartl DM, Bradley PJ, Mendenhall
WM, Suárez C,Takes RP. Cervical lymph node metastases from remote primary tumor sites. Head &
neck. 2016 Apr;38(S1):E2374-85.

5. i) Slow growth rate
ii) Spontaneous involution ( immunodestruction)
iii) Small size
iv) Hidden location ( tonsillar crypts)

6.  Location of lymph nodes
 Lymphatic drainage of the region
 Possible location of the primary tumor (hidden sites)
 Histology of nodes
 Past history (relevant)

7.  Profuse capillary lymphatic network present in
 Paranasal sinuses, middle ear and true vocal cords have
sparse capillary lymphatics
Nasopharynx & Pyriform sinus

8. In evaluating metastatic SCC to cervical lymph nodes, the occult primary is
eventually detected in about half of the cohort.

10.  Detailed history of symptomatology and habits
 Examination of neck
 Thorough clinical examination
 Level of nodal involvement

11.  The mean interval between discovery of a
cervical mass and diagnosis of CUP ranges
from 2 to 5 months.

12.  The lumps are usually located in level 2, followed by level 3, with bilateral
involvement and other symptoms (i.e. pain and dysphagia) reported in less
than 10 per cent.
solid or cystic lesions solitary or multiple lumps.
The usual clinical presentation is of a cervical mass with 3–4 weeks’ progression
Neck lumps

13.  The clinical N stage at presentation is usually N2a, N2b and N2c.
 The presence of cystic malignant metastases in level 2 is often
considered to be a hallmark of human papilloma virus (HPV)-related
squamous carcinoma, usually with subclinical primaries in the
oropharynx.
 It should be also noted that patients presenting with supraclavicular
lymphadenopathy may represent a different clinical entity, due to the
potential for association with infraclavicular neoplasms, such as lung
cancer.

14. If there is no obvious or highly suspicious lesion on
out-patient assessment, then the patient should be
regarded as having an unknown primary and should
be evaluated further, this clinical entity being known
as a ‘clinical’ unknown primary.
Clinical
examination
nose
post-nasal space
oral cavity
oropharynx
larynx
hypopharynx
Including palpation of the oral cavity and
tongue base
The skin and scalp of the head and neck region should be examined to ensure that there are no
significant cutaneous lesions.
If there is an obvious lesion, or high
suspicion of a lesion, then further
management in the form of Imaging and
Panendoscopy of that sub-site should be
carried out.

18. Physical examination
• Careful physical examination
• Fiber-optic evaluation
• Palpation of the oral cavity, oropharynx, and base of the tongue
• Search for scars in the head and neck indicating previous surgery.
• Examination of the neck, which includes site, size, mobility, and relationship
of the node(s) to the adjacent structures.
• Complete physical examination for abnormalities elsewhere: breast,
axilla, groins, testicles, abdomen.

19. • FNAC
• Imaging
• Endoscopy
• Molecular assays
• Examination under General Anaesthesia

20.  FNAC:
To confirm the presence and type of malignancy
 Core biopsy:
If repeated FNAC negative
 Image guided FNAC/Biopsy:
If repeated FNAC negative and in case of a cystic metastasis to get an aspirate
from the wall of the cyst
 IHC
For undifferentiated neoplasms
 EBV detection:
If high probability of nasopharyngeal carcinoma is suspected in view of
ethnicity, bilateral nodes and undifferentiated histology

21.  Lymph-node fine-needle aspiration, preferably under ultra-sound control, is the
first-line examination.
Core biopsy
The advantage of a core biopsy over FNA cytology is that a clearer
HISTOLOGICAL PICTURE can be determined.
Although this is generally used to differentiate between squamous,
thyroid, salivary, breast or bronchial origins, it may be possible from the
cell architecture to suggest the potential origin of the index primary.
Immuno-
histochemical
techniques
May not be able to suggest the TUMOUR ORIGIN they may,
however, potentially exclude sites, e.g. by the use of lung or thyroid
markers. More specific investigations such as identification of
Epstein-Barr virus (EBV) may correlate highly with a nasopharyngeal
site.
Allow detection of the primary in
more than 50% of patients

22. Do not rule out
metastatic lymph
nodes, especially in
case of cystic
presentation, where
the false-negative rate
may be as high as
42% .
A simple means of
confirming differentiated
thyroid cancer is to assay
thyroglobulin. Even in the
absence of tumor cells,
elevated thyroglobulin
confirms neoplasia of
thyroid origin
Trocar biopsy may
be considered in
case ofnegative
findings; the risk
of dissemination
is no more than
0.001%[
Partial lymph-node
resection is not
recommended due
to riskof local
complications and
systemic
dissemination

23. • Head and Neck- CT, MRI
• CECT Thorax
– Trachea
– Oesophagus
– Lungs
• CECT Abdomen
– Liver
– Ovary
– Testes
– Prostate

24.  All patients should have computed tomography (CT) imaging from skull
base to diaphragm as part of the assessment of a newly diagnosed SCC of
the head and neck.
 If the disease presents in a level 2/3 lymph node magnetic resonance
imaging (MRI) of the oropharynx, and in particular the tongue base, tonsil
and tonsil lingual angle, should be carried out.

25. • With negative routine clinical examination, CT, and MRI, PET scan
allows detection of primary tumours in 5-43% of patients.
• Overall staging accuracy -69-78%
• Higher rates of primary tumour detection-non-head and-neck CUP or
histologies other than SCC

26.  Positron emission tomography-computed tomography scanning is the recognised
investigation of choice in the assessment of the unknown primary and has been
shown to be superior to CT scanning alone.
 Recent meta-analysis reported an identification rate of 44 per cent, a sensitivity of
97 per cent and a specificity of 68 percent.
Kwee TC, Kwee RM. Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and
metaanalysis. Eur Radiol 2009;19:731–44
Zhu L, Wang N. 18F-fluorodeoxyglucose positron emission tomography–computed tomography as a diagnostic tool in
patients with cervical nodal metastases of unknown primary site: a meta-analysis. Surg Oncol 2013;22:190–94

27.  According to Miller, PET-CT detects 29% of primaries when CT and MRI
proved negative; linking PET-CT to panendoscopy gave a detection rate of 45%.
Miller FR, Hussey D, Beeram M, EngT, McGuff HS, Otto RA. Positronemission tomography in
the management of unknown primary headand neck carcinoma. Arch Otolaryngol Head Neck
Surg 2005;131:626–9,http://dx.doi.org/10.1001/archotol.131.7.626.
PET coupled to CT (PET-CT) shows better diagnostic efficiency than PET alone, and
is now the reference technique

28. • The resolution of the PET scan limited to 5 mm
• Tumours of the supraglottic region and Waldeyer’ s tonsillar
ring-most difficult to be diagnosed with FDG-PET
– low tumour volume in small, superficial lesions
– the presence of normal lymphoid tissues
• Ideally, biopsies should be performed after PET scan
– Avoids false positive PET-scans at biopsy site.

29. Following each of the clinical and radiological assessments it is necessary to carry out
panendoscopy of the upper aerodigestive tract under general anaesthesia.
Timing

30. vallecula posterior pharyngeal wall

31.  Palpation of oral cavity and tongue base should also be carried out.
 In any of these areas if there is any suspicion of ulceration, change in
colour, asymmetry or fullness, then the area should be photographed and
appropriate deep biopsies taken.

32. Oropharyngeal
LymphoidTissue
Resection
Excision Or SamplingThe
LingualTonsil
RANDOM biopsies ?????

33.  Most current groups would suggest that PET–CT imaging conjunction
with panendoscopy directed biopsy as appropriate and bilateral
tonsillectomy offer the greatest chance of identifying the occult primary
tumour in the routine clinical setting.
 The role of tongue base mucosectomy by transoral laser or robotic
approach, with or without PET–CT or HPV positivity needs prospective
evaluation.
 Following detailed clinical, radiological and operative assessment, if an
index primary site is identified then treatment should be according to the
guidelines for that site with nodal metastasis. If each of these
investigations is negative, then this should be regarded as a ‘true’
unknown primary and the treatment considered as such.

34.  Sequential panendoscopy-tonsillectomy-biopsy is used for squamous cell
CUP.
 Head and neck panendoscopy including nasopharyngeal endoscopy under
general anesthesia is systematic.
 It screens for sometimes millimeter-sized submucosal lesions, notably in
the tonsillar and tongue-base regions, with the help of finger palpation. If
panendoscopy and PET-CT fail to guide biopsy, palatine tonsillectomy
ipsilateral to the metastatic lymph node coupled to tongue-base biopsy is
performed. The aim is to detect submucosal cancer or cancer in the
palatine and lingual tonsil lymphoepithelial crypts; these sites account for
up to 90% of unknown primaries emerging during follow-up.

35.  Tonsillectomy ipsilateral to the metastatic lymph node
provides between18% and 44.6% detection of primaries
 The diagnostic efficiency of palatine tonsillectomy is greater
than that of deep biopsy: 29.5% versus 3.2% (P = 0.0002)
 A recent technique consists in trans oral robotic-assisted or
laser resection of tongue-base lympho epithelial tissue.

36.  A literature review reported 80% primary detection when trans oral
palatine tonsillectomy was associated to lingual tonsillectomy; primaries
were located in the lingual tonsils in 56% of cases. The usefulness of
bilateral palatine tonsillectomy is a subject of discussion. Two studies
reported respectively10% (4/41) and 23% (5/22) primary detection in the
contralateral palatine tonsil. Bilateral palatine tonsillectomy has other
interests: morbidity is low; it resolves clinicians’ doubts in case of
contralateral tonsillar fixation on follow-up PET-CT; and serendipitous
discovery of synchronous primaries has been reported.

37. Epstein-Barr virus (EBV) -nasopharyngeal tumour.
Human Papilloma virus (HPV) - oropharyngeal cancer

38. • Mandatory
• Biopsies taken from all sites suspicious at the clinical and
imaging evaluation
• Or blindly from the sites of possible origin of the primary
o base of tongue
o tonsil or tonsillar fossa
o pyriform sinus
o nasopharynx on the lesion side

39. • Another option is open biopsy
• Increased risk of distant metastases following this procedure
has been suggested
• Detection rate
– CT scan -15-20%
– Panendoscopy with biopsies -up to 65%

40. • The most common sites of primary (82%)
– Tonsil
– Base of tongue
• Bilateral Tonsillectomy, in the absence of suspicious lesions-
up to 25% of primary tumours are detected in this site
• 10% rate of contralateral spread from occult tonsil lesions -
justifies bilateral diagnostic tonsillectomy

41.  The neck is staged as set out elsewhere in this
supplement.
 It should be noted that the correct T stage for an
unknown primary is T0 and not TX.

42. SUMMARY

44. Management
• Surgery
• Radiation
• Chemotherapy
• Combination
• The choice of the treatment schedule
depends on the histology and on the stage of the disease.

45.  Most treatment regimens will therefore involve combined modality
treatment, but on occasions, radiotherapy (RT), and even more rarely
surgery, will be used as single modality treatment.
 The rate of emergence of the primary tumour is approximately 3 per cent
per year, which is equivalent to the development of second carcinomas in
the head and neck, lung and oesophagus.
 Therefore the primary aim of treatment is locoregional control..
Curative with the least morbidity to the upper aerodigestive tract
possible.

46.  Surgery on its own may be sufficient treatment for N1 necks demonstrating no
extracapsular spread, but in all other scenarios, needs to be supplemented by
adjuvant (chemo) radiation
 For more advanced neck disease intensive combined treatment is required.
This could be either a combination of neck dissection and RT or initial
(chemo)- radiotherapy followed by planned neck dissection if a complete
response is not evident on imaging. Both of these approaches appear to be
equally effective.

47. May be treated with surgery alone provided the
surgery has been comprehensive.
This has been shown to be as effective as RT and
clearly avoids the potential side effects of RT.
There are no randomiseddata to support MRND
over selective neck dissection(SND).13
RT to at least the involved nodal levels is
necessary, although it is more usual to irradiate
the entire ipsilateral post-operative neck, and
boost the involved levels.
There are also some reports that locoregional
tumour control is up to 40 per cent higher with
surgery and radiation therapy compared with
radiation alone, meaning radiation alone, even
for N1 disease, must remain an option only for
those who are inoperable on medical grounds
or where it is considered appropriate for those
who are HPV positive.
T0N1 – no extracapsular spread T0N1 – with extracapsular spread.

48.  For each of these stages comprehensive clearance of the involved lymph
node levels is usually required in the form of MRND or SND with possible
contralateral SND or MRND.
 Radical RT to one or both sides of the neck should be considered, even for
pN2a disease, as in one of the largest series of occult primary head and
neck cancer in 136 patients from the MD Anderson Centre, combined
surgery and post-operative radiation was associated with lower rates of
locoregional relapse and higher disease-free survival. This radiation may
be given with or without concomitant chemotherapy as described above.
While there remains no randomised data to support the use of
chemotherapy for pN2 disease from an occult head and neck primary, there
are two case series both demonstrating excellent progression- free survival
(PFS) and overall survival (OS) rates. The chemotherapy protocols used
were heterogeneous, and included concomitant cisplatin, concomitant 5-
fluorouracil (5-FU) and hydroxyurea, as well as paclitaxel.

49.  It may not be possible to have a curative aim in patients with
this staging.
 For curative intent a radical neck dissection or Type I MRND
with postoperative chemoradiotherapy will usually be necessary.

50.  Primary treatment.
 For N1 disease with extracapsular spread, N2 and N3 disease, initial
chemoradiation with planned neck dissection only for those patients not
achieving a clinical or metabolic complete response on post-treatment
imaging is a valid management strategy.
 The extent of the RT fields to be treated is controversial
 In the absence of high-level evidence, the practice of radiation therapy in
this setting includes involved field only or bilateral neck and TMI.
 The latter is practiced commonly in the UK.

53.  Post-operative neck: 60 Gy in 30 fractions or equivalent
 Post-operative neck with extracapsular spread: 64–66 Gy in 32–33
fractions or equivalent
 Gross macroscopic disease still present: 70 Gy in 30 fractions or
equivalent
 Putative mucosal sites and the uninvolved neck: 50 Gy in 25 fractions or
equivalent.

54.  There is a lack of consensus on the RT target volumes that should be
treated after neck dissection.
 Treatment of the ipsilateral hemi-neck alone is of considerably lower
toxicity and has been shown to achieve local control rates in the cervical
nodes of 90 per cent with contralateral relapse rates as low as 4.7 per cent,
provided treatment strategies are determined using PET–CT.
 However, total mucosal and bilateral neck irradiation of the head and neck
region is a common practice with the aim of eradicating the primary and
the microscopic neck disease.
 With the addition of cisplatin to primary RT for the treatment of head and
neck cancer, an absolute survival benefit of 6.5 per cent is seen at five
years.

55.  Investigating concomitant chemoradiation in the postoperative setting, the
Radiation Therapy Oncology Group (RTOG) demonstrated a 10 per cent
improvement in locoregional control rate, and a 22 per cent risk reduction
of disease recurrence and death at two years, while the European
Organisation for Research and Treatment of Cancer (EORTC) group
showed a 13 per cent improvement in locoregional control, 25 per cent risk
reduction of disease progression, and 30 per cent risk reduction of death at
five years.
 These findings were based on the concomitant use of cisplatin 100 mg/m2
on days 1, 22 and 43,whichmust therefore remain the gold standard.
Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH et al. Postoperative irradiation with or without concomitant
chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945–52
Cooper JS, PajakTF, ForastiereAA, Jacobs J, Campbell BH, Saxman SB et al. Postoperative concurrent radiotherapy and chemotherapy for
high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937–44

56.  This remains a controversial issue.
 In the largest series to date, no patient developed a metachronous primary
in the follow-up period, and so would have experienced only toxicity
rather than benefit from TMI.
 Some groups have recommended bilateral neck and TMI for occult
primary head and neck cancer patients, claiming improved local control,
but no OS benefit. There is no conclusive evidence to support the routine
use of TMI.

57. Frank SJ, Rosenthal DI, Petsuksiri J, Ang KK, MorrisonWH,Weber RS et al. Intensity-modulated
radiotherapy for cervical node squamous cell carcinoma metastases from unknown head and-
neck primary site: M. D. Anderson cancer center outcomes and patterns of failure. Int J Radiat
Oncol Biol Phys 2010;78:1005–10
MD Anderson group
5 year
locoregional control
of 94 per cent
OS of 89 per cent.
Four centres have reported their experience of using IMRT to deliver TMI for unknown
primaries, with excellent two-year locoregional control (85–88 per cent) and OS (74–85 per
cent).

58.  The chemotherapy regimen used is at the discretion of the treating
clinician, but will usually be platinum-based, single-agent cisplatin or
carboplatin or cetuximab in patients with suboptimal renal function

59.  While the meta-analysis of chemotherapy in head and neck cancer
(MACHNC) failed to demonstrate a significant benefit for the use of
induction chemotherapy, many of the historical trials included pre-dated the
use of taxanes.
Both the EORTC 24971 and TAX 323 studies
and the TAX 324 trial found that the addition of
docetaxel (T) to cisplatin (P) and 5-FU resulted
in improved PFS, OS and response rate and yet
lower associated toxicity.
In the context of gross unresectable neck disease,
it therefore seems reasonable to consider the use
of such induction chemotherapy, particularly for
patients with excellent performance status, as a
cytoreductive measure prior to definitive
concomitant chemoradiation, even for occult
primary disease.

60.  Adjuvant chemotherapy.
 There are no convincing data that chemotherapy given after radiation or
surgery is of benefit in terms of either disease-free or OS for patients with
detectable primaries. This approach cannot therefore be recommended for
patients with occult primary head and neck cancer.

61. • Platinum based chemotheraptic agents are used.
• Cisplatin at 100 mg/m2, and 5-fluorouracil(5-
FU) at 400 mg/m2.
• Chemoradiation conducted with high-dose
cisplatin at 100 mg/m2 once per three weeks
during the period of radiotherapy
HungYH, Liu SA, Wang CC, Wang CP, Jiang RS, Wu SH.Treatment outcomes of unknown primary squamous cell
carcinoma of the head and neck. PloS one. 2018;13(10).
Chemotherapy regimen

62. 1)Stage
 N1/N2-N3
2) Level of LN

I/II-III-upper V/IV/lower level V
3)Presence of extracapsular extension

If present chemotherapy to be added

67. 
 By using IMRT the degree of toxicity can be
reduced compared with conventional methods.
 High OS, DFS, and nodal control can be achieved for
patients with T0N1 or T0N2a disease without
extracapsular spread.
 Patients with extracapsular spread or bulky T0N2b–c
or T0N3 disease have a worse prognosis and may
benefit from the addition of more cytotoxic
chemotherapy,molecular targeted therapy, and/or
accelerated radiation regimens.
Kamal M, MohamedAS, Fuller CD, Sturgis EM, Johnson FM, MorrisonWH, GunnGB, Hutcheson KA, Phan J,Volpe S,
Ng SP. Outcomes of patients diagnosed with carcinoma metastatic to the neck from an unknown primary source
and treated with intensity‐modulated radiation therapy. Cancer. 2018 Apr 1;124(7):1415-27.

68.  All patients presenting with confirmed cervical lymph node metastatic
squamous cell carcinoma and no apparent primary site should undergo:
 ○ Positron emission tomography-computed tomography whole-body scan. (R)
 ○ Panendoscopy and directed biopsies. (R)
 ○ Bilateral tonsillectomy. (R)
 Tongue base mucosectomy can be offered if facilities and expertise exists. (G)

69.  Concomitant chemotherapy with radiation should be considered in patients with an
unknown primary. (R)
 Concomitant chemotherapy with radiation should be offered to suitable patients in
the post-operative setting, where indicated.
 Neo-adjuvant chemotherapy can be used in gross ‘unresectable’ disease. (R)
 Patients should be followed up at least two months in the first two years and three
to six months in the subsequent years. (G)
 Patients should be followed up to a minimum of five years with a prolonged follow
up for selected patients. (G)
 Positron emission tomography–computed tomography scan at three to four months
after treatment is a useful follow-up strategy for patients treated by chemoradiation
therapy. (R)

70.  Thank you